CHARACTERIZATION, BEHAVIOR AND PLASTICITY OF PLURIPOTENT STEM CELLS

RELEASE DATE:  May 4, 2004

PA NUMBER:  PA-04-101

The R01 portion of this funding opportunity has been replaced by PA-07-201,
which now uses the electronic SF424 (R&R) application for February 5, 2007 
submission dates and beyond.

March 2, 2006 (NOT-OD-06-046) – Effective with the June 1, 2006 submission date, 
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using 
the electronic SF424 (R&R) application. Accordingly, this funding opportunity 
expires on the date indicated below. A replacement R21 (PA-06-198) funding 
opportunity announcement has been issued for the submission date of June 1, 2006 
and submission dates thereafter. 

See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and 
AIDS-related R03 and R21 Applications.

Expiration Date for R21 Non-AIDS Applications: March 2, 2006
Expiration Date for R21 AIDS and AIDS-Related Applications: May 2, 2006 
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

Department of Health and Human Services (DHHS)

PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
 (http://www.nih.gov)

COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Neurological Disorders and Stroke (NINDS)
 (http://www.ninds.nih.gov)
National Institute on Deafness and Other Communication Disorders (NIDCD)
 (http://www.nidcd.nih.gov/)
National Institute on Aging (NIA)
 (http://www.nia.nih.gov/)
National Institute of Child Health and Human Development (NICHD)
 (http://www.nichd.nih.gov/)
National Cancer Institute (NCI)
 (http://www.nci.nih.gov/)
National Institute on Drug Abuse (NIDA) 
 (http://www.nida.nih.gov)
National Institute of Mental Health (NIMH)
 (http://www.nimh.nih.gov/)

CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: NINDS 93.853, NIDCD 93.173, 
NIA 93.866, NICHD 93.929, NCI 93.396, NIDA 93.279, and NIMH 93.242. 
  
THIS PA CONTAINS THE FOLLOWING INFORMATION

o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations

PURPOSE

Stem cells appear to possess great plasticity, but the cellular mechanisms 
regulating their behavior and fate are not understood. If these mechanisms 
can be harnessed to obtain cells specifically required for therapy, diagnosis 
or drug discovery, it may be possible to restore function to tissues and 
organ systems that have been compromised by congenital disorders, 
developmental malfunction, age, injury, disease or drug exposure. The 
National Institute of Neurological Disorders and Stroke (NINDS), the National 
Institute on Deafness and Other Communication Disorders (NIDCD), the National 
Institute on Aging (NIA), the National Institute of Child Health and Human 
Development (NICHD), the National Cancer Institute (NCI), the National 
Institute of Drug Abuse (NIDA), and the National Institute of Mental Health 
(NIMH) invite applications for studies on the characterization, behavior and 
plasticity of human and non-human stem cells, regulation of their 
replication, differentiation, integration and function in the nervous system, 
and the identification and characterization of normal and tumor stem cells. 
An understanding of intrinsic and extrinsic signals, especially those 
involved in the stem cell niche, age-dependent processes and genetic factors 
that govern the activities of pluripotent cells is crucial in order to 
utilize them to develop safe and effective treatments for the restoration of 
function, or to prevent their transformation into tumor-generating cells. 
Although animal studies demonstrate that stem or progenitor cells can be 
derived from a variety of tissues and from hosts of different ages, the 
requirements and potential for differentiation of each type of pluripotent 
cell appear to be unique. We lack a clear understanding of the intrinsic 
properties that distinguish one population from another, and how these 
populations differ in their response to similar conditions in vitro and in 
vivo. This Program Announcement, which replaces PA-01-078 (Biology of Non-
Human Stem Cells in the Environment of the Nervous System) and PA-02-025 
(Plasticity of Human Stem Cells in the Nervous System), encourages 
applications to study the fundamental properties of all classes of human and 
non-human stem cells, and to confirm, extend, and compare the behavior of 
stem cells that are derived from different sources and ages or exposed to 
different regimes in vitro and in vivo or derived from tumors. Of high 
priority are studies to develop methods for identifying, isolating and 
characterizing specific precursor populations at intermediate stages of 
differentiation into neurons and glia, and their relationship to tumor-
generating cells. Projects that address comparisons between different classes 
of human stem cells and between human and non-human stem cells would also be 
directly relevant to this PA.

RESEARCH OBJECTIVES

Background

Stem cell research offers enormous potential for treating a host of 
congenital, developmental, psychiatric or degenerative diseases for which 
there are no cures. In animal studies, multipotent progenitor cells from many 
different sources have been reported to generate cells with neuronal or glial 
properties, raising expectations that they could be used to replace lost 
neurons and glia, repair defective circuits, and restore functions 
compromised by abnormal development, age, physical damage, disease or drug 
addiction. In addition to cell and tissue therapy, the ability to selectively 
produce one or more differentiated cell types at will from pluripotent stem 
cells would be of clinical importance in investigating the effects of drugs, 
environmental and genetic factors on differentiation and cell function in the 
human nervous system. These approaches could aid in the discovery of drugs 
and ultimately in the development of a variety of effective treatment 
strategies. 

Major challenges have to be overcome before any type of stem cell can be 
harnessed and translated to meaningful treatments for patients.  These 
challenges include identifying the optimal type of stem cell or stem cell 
derivative for specific assays and therapies for individual disorders, 
harvesting and growing sufficient quantities of the appropriate cell type, 
deciding the best therapeutic strategy for each condition to be treated, and 
assessing the potential side effects that may arise when such versatile cells 
are introduced into a patient. In addition, examples of the enormous 
plasticity exhibited by stem cells raise fundamental questions about the 
comparative potential for differentiation of precursor cells derived from 
different sources and different stages of development, the nature of the 
conditions that regulates stem cell behavior, and the genetic, molecular and 
cellular mechanisms that result in functional integration within the nervous 
system over the lifespan of the host. 

Of the many types of progenitor cells competent to develop neuronal and glial 
features, embryonic stem (ES) cells, derived from embryos at the blastocyst 
stage, may have the broadest natural potential for differentiation because, 
during development, they normally produce all the cells of an organism. These 
pluripotent cell lines are characterized by nearly unlimited self-renewal and 
differentiation capacity.  During differentiation in vitro, mouse and human 
ES cells express properties of mature tissues such as muscles, several 
classes of neurons, glia, pancreatic islet cells, cartilage and blood. When 
transplanted into the central nervous system (CNS), ES cells that have been 
coaxed along an oligodendrocytic lineage will form myelin and ensheath axons. 
Some improved function was reported in rodent models of demyelination and 
spinal cord injury that received these ES cell-derived transplants. However, 
how the transplanted cells contributed to the restoration of function is 
unclear.     

Other sources of progenitors are neural stem cells that are derived from 
neurogenic regions in the developing and adult CNS. They integrate seamlessly 
into the host when transplanted into the developing nervous system, but their 
fate appears highly dependent upon the local environment that they encounter. 
This is particularly true when these cells are introduced into the adult CNS.  
For example, cells that can become neurons in one part of the nervous system, 
such as the hippocampus, generate astrocytes exclusively when placed into the 
spinal cord. The concept of the niche has emerged recently as an important 
one; yet at the present time, we have very little information on the nature 
of the environmental signals that regulate fate decisions of stem cells.  

Of particular interest are recent reports from a number of investigators that 
stem cells present in adult, non-neuronal tissues appear to show surprising 
plasticity or versatility.  For example, under specific culture conditions, 
bone marrow stromal cells appear to “trans-differentiate” to give rise to 
cells with neuronal or glial features.  Following bone marrow 
transplantation, donor-derived cells could be found in many tissues including 
the CNS, skeletal muscle, liver, heart, vascular endothelia, and bone. Some 
of these findings have been attributed to the fusion of a donor cell with a 
mature host cell, giving the appearance of trans-differentiation of the donor 
cell to an unrelated adult phenotype. Other reports of switches in lineage 
cannot be explained by fusion.  Perhaps most intriguing is the hypothesis 
that cells committed to a particular lineage may “de-differentiate” to a more 
pluripotent state.  One of the most attractive sequelae of plasticity is the 
possibility of developing autologous cells for transplantation, because 
autologous grafts will not be rejected by the host or recipient. On the other 
hand, the pliable nature of stem cells raises the concern that transplanted 
cells could be triggered by the local environment to an undesired phenotype 
with unpredictable consequences. Before we can design therapies using human 
stem cells, we must understand how "plastic" or malleable are these different 
classes of cells, the signals that drive their choice of fates, and how 
reversible are these fates.    

For unknown reasons, select populations of cells are destroyed in specific 
neurological disorders and diseases - dopaminergic neurons in Parkinson's 
Disease (PD), cholinergic neurons in Alzheimer's Disease(AD), motor neurons 
in Amyotrophic Lateral Sclerosis (ALS) and myelinating oligodendrocytes in 
Multiple Sclerosis (MS). Because there is great diversity of neurons and 
glia, studies to develop treatments for these and other diseases with less 
well defined etiologies will require the characterization and acquisition of 
unique populations of neurons and glia. While dopaminergic neurons are 
clearly the target of studies on PD, defining the specific features of the 
dopaminergic neurons needed to treat PD is less obvious.  Each neuronal and 
glial phenotype is defined by a constellation of morphological, biochemical, 
genetic, and electro-physiological properties, and the functional 
significance or impact of a neuronal population depends on connectivity with 
appropriate afferent and efferent populations. It is necessary to determine 
the optimal stem cell and protocol that will produce a differentiated 
phenotype that best replicates the significant properties required and can 
replace the dysfunctional cell type. The features most commonly evaluated 
include morphology, biochemical and gene expression, and physiology.  Less 
often described are quantification of protein and gene levels, acquisition 
and maintenance of phenotype over time, cell division and migration, and the 
simultaneous tracking of multiple properties in a population of cells.  Least 
studied are the integration and functional consequences of the transplanted 
cells in the host, and the long-term behavior of the transplanted population. 
In summary, because we know little about the biology and the comparative 
scope for differentiation of the many different types of stem cells, it is 
difficult to assess realistically their potential for use in developing 
treatments for neurological disease and other conditions.  

Recent findings demonstrate that in select regions of the avian and mammalian 
nervous systems, endogenous neural stem and precursor cells continue to 
produce new neurons and circuits throughout adulthood, and indeed over the 
entire lifespan, though new cell production declines with age. In the adult 
hippocampus, newly born neurons acquire the size and morphology of their 
older neighbors and establish contacts with existing circuits in the brain, a 
process that can take months to complete. Endogenous stem cells can replace 
hair cells of the inner ear following acoustic and drug-induced damage in the 
adult avian and amphibian nervous systems. Similarly, the sensory neurons of 
the olfactory epithelium are replaced on a regular basis, and especially in 
response to injury, from an endogenous stem cell pool. Behavior, experience 
and drugs such as anti-depressants have demonstrable and profound effects on 
the production and establishment of new neurons in the adult and the aging 
brain. Drug abuse, on the other hand, have been shown to inhibit neurogenesis 
in rodents and result in developmental deficits and cognitive dysfunctions in 
humans and animals.  All these findings have important implications for 
development, learning, memory and the maintenance of a healthy nervous system 
that functions throughout life.  New research into mechanisms that influence 
ongoing neurogenesis and gliogenesis will provide fundamental information on 
the capacity of the nervous system to adapt in response to pharmacological 
and behavioral therapy throughout life. The hope is that processes that 
regulate the native production and integration of new neurons may be deployed 
to repair disordered regions of the brain.

Objectives and Scope

This Program Announcement is intended to promote studies of stem cell 
biology and the regulation and control of stem cells in the nervous system.   
Research efforts on characteristics that distinguish between different types 
of stem cells and the cellular, molecular and genetic mechanisms that 
influence their lineage choices are particularly relevant, as are studies 
that explore the long-term fates of stem cell-derived populations in animal 
models. Also of interest is the development of methods for isolating specific 
cell populations, and studies that demonstrate or enhance the safety of stem 
cells in treatments for neurological conditions. The following examples 
illustrate areas that are of high interest; other innovative projects are 
also encouraged.

o Comparison of the mitotic potential and fates of different types of 
pluripotent, progenitor cells in vitro and in vivo.

o Comparison of the migratory properties and structural and functional 
integration of different types of progenitor cells in the developing, adult 
or aging host nervous system.

o Comparison of the behavior of human stem cells with that of their non-
human counterparts in vitro and in vivo.

o Investigation of the ability of different types of stem cells or of 
partially differentiated cells to revert to a more plastic, multipotent 
state, under normal conditions and following injury, disease or drug 
exposure.

o Examination of changes in gene and protein expression as human and animal 
stem cells differentiate along specific lineages.

o Identification of signals, signaling pathway components and transcriptional 
factors that regulate the fate(s) of transplanted stem cells and their 
progeny in the nervous system of the host.

o Development of markers and assays (in vitro and in vivo) that permit 
accurate and reliable characterization of the state of differentiation of 
human and non-human stem or neural precursor cells.

o Development of methods for identifying, isolating and enriching select 
precursor populations, intermediate states, and differentiated neuronal and 
glial phenotypes.  

o Development of a public database of gene expression patterns for human and 
non-human stem cells as they self-renew or develop and mature into specific 
neuronal and glial fates.  

o Use of animal model systems of neurological and neuropsychiatric disorders 
and of drug addiction for screening and comparing the functional capabilities 
of implanted stem cells and their progeny.

o Assessment of the ability of transplanted cells to integrate with the adult 
and aging host nervous system and modify dysfunctional states.

o Assessment of the long-term fates and the consequences of transplanted 
cells and their progeny in the nervous system, and in ectopic sites within 
the host. 

o Assessment and comparison of the immune responses generated by different 
human stem cells and their progeny in the host.

o Assessment of the behavior of host cells in response to the short-term and 
long-term presence of transplanted human stem cells and/or their derivatives.

o Comparison of the efficacy and risks of different modes of cell delivery in 
large and small mammals, and in animals of different ages.

o Development of novel techniques such as non-invasive methods to track the 
location, phenotype, integration and/or function of transplanted stem cells 
and their progeny.

o Assessment of the effects of environmental changes, therapies, or 
rehabilitation strategies on the production, differentiation and survival of 
endogenous stem cells across the lifespan. 
 
MECHANISM OF SUPPORT

The Exploratory/Developmental Grants (R21) mechanism and the Research Project 
(R01) grant mechanism will be used to support projects under this Program 
Announcement (PA).  Under these mechanisms, responsibility for the planning, 
direction, and execution of the proposed project will be solely that of the 
applicant.  The proposed project period during which the research will be 
conducted should adequately reflect the time required to accomplish the 
stated goals and should be no more than 5 years for R01 grants.  The R21 
mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) 
is intended to encourage exploratory and developmental research projects by 
providing support for the early and conceptual stages of these projects. 
These one-time awards support innovative, high impact research projects that 
1) assess the feasibility of a novel area of investigation or a new 
experimental system, 2) include the unique and innovative use of an existing 
methodology to explore a new scientific area, 3) involve considerable risk 
but may lead to a breakthrough in a particular area, or 4) develop new 
technology or methodology that could have major impact in a specific research 
area.  Applications for R21 awards should describe projects distinct from 
those supported through the traditional R01 mechanism.  For example, long-
term projects, or projects designed to increase knowledge in a well-
established area will not be considered for R21 awards.  Applications 
submitted under this mechanism should be exploratory and novel.  These 
studies should break new ground or extend previous discoveries toward new 
directions or applications.

R21 applications may request a project period of up to two years with a 
combined budget for direct costs of up to $275,000 for the two year period.  
For example, you may request $100,000 in the first year and $175,000 in the 
second year.  The request should be tailored to the needs of your project.  
Normally, no more than $200,000 may be requested in any single year.  For 
further information on the R21 mechanism, including Institute-specific 
information,see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.

This PA uses just-in-time concepts.  It also uses the modular budgeting as 
well as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular budget format.  Otherwise follow the instructions 
for non-modular budget research grant applications.  

ELIGIBLE INSTITUTIONS 

You may submit (an) application(s) if your institution has any of the 
following characteristics:
   
o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS

Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with their institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs. 

SPECIAL REQUIREMENTS

Use of human embryonic stem cells (hESCs): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
All cell lines that meet these criteria and are therefore eligible for 
research with federal funding are identified and registered in the NIH Human 
Embryonic Stem Cell Registry (http://escr.nih.gov).  NIH has established a 
website (http://stemcells.nih.gov/info/faqs.asp) that provides 
information in the form of answers to frequently asked questions about 
implementation issues for human embryonic stem cell research (see also: 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-014.html). Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for funding.  Each approved cell line is 
specifically identified by an NIH code in the Registry.  It is the 
responsibility of the applicant to provide in the Description (page 2) of 
their application the official NIH identifier(s) for the hESC line(s) that 
they will use as found in the NIH Registry (http://escr.nih.gov).  
Applications that do not provide this information will be returned without 
review.

Plan for Dissemination of Data and Biomaterials: Sharing of biomaterials, 
data, and software in a timely manner is essential for rapid progress in 
biomedical research.  All applicants who respond to this PA must propose 
plans for sharing data and biomaterials generated through the grant.  PHS 
policy requires that investigators make unique research resources available 
for research purposes to qualified individuals within the scientific 
community when they have been published (see the NIH Grants Policy Statement 
at http://grants.nih.gov/grants/guide/notice-files/not96-184.html).
 
In addition, NIH recently released a statement on the sharing of research 
data that applies to all investigator-initiated applications with direct 
costs greater than $500,000 in any single year 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html).

The Initial Review Group will evaluate the proposed sharing plan and comment 
on its adequacy in an administrative note in the summary statement.  
Reviewers will not factor the proposed data-sharing plan into the 
determination of scientific merit or priority score.  The adequacy of the 
plan will be considered by NIH staff in determining whether the grant shall 
be awarded.  The sharing plan as approved, after negotiation with the 
applicant when necessary, will be a condition of the award.

WHERE TO SEND INQUIRIES

We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Arlene Y. Chiu, Ph.D.
Program Director, Repair and Plasticity Program
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2206, MSC 9525
Bethesda, MD  20892-9525
Telephone:  (301) 496-1447
FAX: (301) 480-1080
Email:  chiua@ninds.nih.gov

Barry J. Davis, Ph.D.
Division of Scientific Programs
NIDCD / Suite 400C
6120 Executive Blvd., MSC 7180
Rockville, MD  20892-7180
Phone:  301-402-3464
FAX: 301-402-6251
Email: Davisb1@nidcd.nih.gov

Bradley C Wise, Ph.D.
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 350
7201 Wisconsin Avenue MSC 9205
Bethesda, MD 20892-9205
Telephone:   (301) 496-9350
FAX:   (301) 496-1494
Email: WiseB@nia.nih.gov
 
Ralph M. Nitkin, Ph.D.
Biological Sciences and Career Development Program
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Executive Building, Room 2A03
6100 Executive Blvd, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 402-4206
FAX: (301) 402-0832
Email: rn21e@nih.gov

Neeraja Sathyamoorthy, Ph.D. 
Program Director 
Tumor Biology & Metastasis Branch 
Division of Cancer Biology 
National Cancer Institute 
6130 Executive Boulevard EPN 5036 
Rockville MD 20892
Phone: 301-435-1878 
Fax: 301-480-0864 
Email: ns61r@nih.gov

Geraline C. Lin, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard
Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone:  (301) 435-1305
FAX: (301) 594-6043
Email: glin@nida.nih.gov

Beth-Anne Sieber, Ph.D.
Chief, Developmental Neurobiology Program
National Institute of Mental Health
Division of Neuroscience and Basic Behavioral Science
6001 Executive Boulevard, Rm 7186
Bethesda, MD  20892-9641
Phone: (301) 443-5288
Fax: (301) 402-4740
E-mail: bsieber@mail.nih.gov

o Direct your questions about financial or grants management matters to:

Michael J. Loewe
Chief, Grants Management Branch
National Institute of Neurological Disorders and Stroke 
6001 Executive Blvd., Suite 3290, MSC 9537
Bethesda, MD  20892-9537
Telephone: (301) 496-9231 
FAX: (301) 402-0219
Email: ml70m@nih.gov

Or to 

Gavin Wilkom
Grants Management Specialist
Grants Management Branch, DER 
National Institute of Neurological Disorders and Stroke
Neuroscience Center, 6001 Executive Blvd. Room 3250, MSC 9537
Bethesda MD, 20892
Telephone: (301) 496-7480
FAX: 301-402-0219
Email: gw62m@nih.gov

Sara Stone
Chief, Grants Management Office
Division of Extramural Activities
NIDCD / Suite 400B
6120 Executive Blvd, MSC-7180
Bethesda, MD  20892-7180
Telephone:  (301)402-0909
FAX:  (301) 4021758
Email:  stones@nidcd.nih.gov

Linda Whipp
Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212 MSC9205
Bethesda, Maryland 20892-9205
Telephone:   (301) 496-1472
Email:WhippL@nia.nih.gov

Chris Robey 
Grants Management Branch 
National Institute of Child Health and Human Development 
6100 Executive Boulevard, 8A17, MSC 7510 
Bethesda, MD 20892-7510 
Telephone: (301) 435-6996 
FAX: (301) 451-5510 
Email: robeyj@mail.nih.gov

Bill Wells
Grants Administration Branch
National Cancer Institute
EPS Room 243
6130 Executive Boulevard
Rockville MD 20892
Phone: 301-496-8796
Email: wellsw@mail.nih.gov

Diana Haikalis 
Acting Team Leader
Grants Management Branch
National Institute on Drug Abuse 
6101 Executive Boulevard 
Room 270 MSC 8403
Bethesda, MD 20892-8403
Telephone: (301) 443-6710 
Email: dhaikali@nida.nih.gov

Rebecca Claycamp, CRA
Chief Grants Management Officer
National Institute of Mental Health
6001 Executive Boulevard, Room 6122, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2811
FAX: (301) 443-6885
Email: rc253d@nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and 
Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the 
Universal Identifier when applying for Federal grants or cooperative 
agreements. The DUNS number can be obtained by calling (866) 705-5711 or 
through the web site at http://www.dunandbradstreet.com/. The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 
398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html 
in an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

The title and number of this program announcement must be typed on line 2 of 
the face page of the application form and the YES box must be checked.

SUPPLEMENTARY INSTRUCTIONS:  All instructions for the PHS 398 (rev. 5/2001) 
must be followed, with these exceptions:

o Description (page 2)

The NIH identifier(s) of the hESC line(s) to be used must be included.

o   Research Plan

For R21 applications only, items a – d of the Research Plan (Specific Aims, 
Background and Significance, Preliminary Studies, and Research Design and 
Methods) may not exceed a total of 15 pages.  No preliminary data is required 
for R21 proposals, but may be included if it is available.  Please note that 
a Progress Report is not needed for R21 awards; competing continuation 
applications for an exploratory/developmental grant will not be accepted.

Appendix.  Use the instructions for the appendix detailed in the PHS 398 
except that for R21 applications, no more than 5 manuscripts, previously 
accepted for publication, may be included.

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at http://grants.nih.gov/grants/dates.htm.  Application 
deadlines are also indicated in the PHS 398 application kit.

SPECIFIC INSTRUCTIONS FOR MODULAR BUDGET GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in a 
modular budget grant format.  The modular budget grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
   
1) Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your         
application for consideration for award; and,
  
3) Identify, in a cover letter sent with the application, the staff member       
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt 
dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an unfunded version of an application 
already reviewed, but such application must include an Introduction 
addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding 
assignment within 8 weeks.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.   Appropriate scientific review groups 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council 
or board  

REVIEW CRITERIA

The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to evaluate application in 
order to judge the likelihood that the proposed research will have a 
substantial impact on the pursuit of these goals.  The scientific review 
group will address and consider each of the following criteria in assigning 
the application’s overall score, weighting them as appropriate for each 
application.

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The application does not need to be strong in all categories to be judged 
likely to have major scientific impact and thus deserve a high priority 
score.  For example, an investigator may propose to carry out important work 
that by its nature is not innovative but is essential to move a field 
forward.

SIGNIFICANCE: Does this study address an important problem? If the aims of 
the application are achieved, how will scientific knowledge be advanced?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

APPROACH: Are the conceptual framework, design, methods, and analyses 
adequately developed, well-integrated, and appropriate to the aims of the 
project?  Does the applicant acknowledge potential problem areas and consider 
alternative tactics?

INNOVATION: Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing 
paradigms or develop new methodologies or technologies?

INVESTIGATOR: Is the investigator appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to the experience 
level of the principal investigator and other researchers (if any)?

ENVIRONMENT: Does the scientific environment in which the work will be done 
contribute to the probability of success?  Do the proposed experiments take 
advantage of unique features of the scientific environment or employ useful 
collaborative arrangements?  Is there evidence of institutional support?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following 
items will be considered in the determination of scientific merit and the 
priority score:

PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human 
subjects and protections from research risk relating to their participation 
in the proposed research will be assessed. (See criteria included in the 
section on Federal Citations, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of 
plans to include subjects from both genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals of the 
research will be assessed.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to 
be used in the project, the five items described under Section f of the PHS 
398 research grant application instructions (rev. 5/2001) will be assessed.  

ADDITIONAL REVIEW CONSIDERATIONS 

Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, 
reviewers will not factor the proposed data sharing plan into the 
determination of scientific merit or priority score. 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:  

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities

REQUIRED FEDERAL CITATIONS 

HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated with 
reference to the risks to the subjects, the adequacy of protection against 
these risks, the potential benefits of the research to the subjects and 
others, and the importance of the knowledge gained or to be gained. 
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for 
all types of clinical trials, including physiologic, toxicity, and dose-
finding studies (phase I); efficacy studies (phase II), efficacy, 
effectiveness and comparative trials (phase III). The establishment of data 
and safety monitoring boards (DSMBs) is required for multi-site clinical 
trials involving interventions that entail potential risk to the 
participants.    (NIH Policy for Data and Safety Monitoring, NIH Guide for 
Grants and Contracts, June 12, 1998: 
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).  

SHARING RESEARCH DATA: Investigators submitting an NIH application seeking 
$500,000 or more in direct costs in any single year are expected to include a 
plan for data sharing or state why this is not possible. 
http://grants.nih.gov/grants/policy/data_sharing  Investigators should seek 
guidance from their institutions, on issues related to institutional 
policies, local IRB rules, as well as local, state and Federal laws and 
regulations, including the Privacy Rule. Reviewers will consider the data 
sharing plan but will not factor the plan into the determination of the 
scientific merit or the priority score.

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of 
the NIH that women and members of minority groups and their sub-populations 
must be included in all NIH-supported clinical research projects unless a 
clear and compelling justification is provided indicating that inclusion is 
inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing clinical research should read the "NIH Guidelines 
for Inclusion of Women and Minorities as Subjects in Clinical Research - 
Amended, October, 2001," published in the NIH Guide for Grants and Contracts 
on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical 
research; updated racial and ethnic categories in compliance with the new OMB 
standards; clarification of language governing NIH-defined Phase III clinical 
trials consistent with the new PHS Form 398; and updated roles and 
responsibilities of NIH staff and the extramural community.  The policy 
continues to require for all NIH-defined Phase III clinical trials that: a) 
all applications or proposals and/or protocols must provide a description of 
plans to conduct analyses, as appropriate, to address differences by 
sex/gender and/or racial/ethnic groups, including subgroups if applicable; 
and b) investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 
differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: 
The NIH maintains a policy that children (i.e., individuals under the age of 
21) must be included in all human subjects research, conducted or supported 
by the NIH, unless there are scientific and ethical reasons not to include 
them. 

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH 
policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at http://stemcells.nih.gov/index.asp and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide, in the project 
description and elsewhere in the application as appropriate, the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 
review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The 
Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances.  Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA.  It is important for applicants to understand the basic scope 
of this amendment.  NIH has provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION:  The 
Department of Health and Human Services (DHHS) issued final modification to 
the “Standards for Privacy of Individually Identifiable Health Information”, 
the “Privacy Rule,” on August 14, 2002.  The Privacy Rule is a federal 
regulation under the Health Insurance Portability and Accountability Act 
(HIPAA) of 1996 that governs the protection of individually identifiable 
health information, and is administered and enforced by the DHHS Office for 
Civil Rights (OCR).  

Decisions about applicability and implementation of the Privacy Rule reside 
with the researcher and his/her institution. The OCR website 
(http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including 
a complete Regulation Text and a set of decision tools on “Am I a covered 
entity?”  Information on the impact of the HIPAA Privacy Rule on NIH 
processes involving the review, funding, and progress monitoring of grants, 
cooperative agreements, and research contracts can be found at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals 
for NIH funding must be self-contained within specified page limitations. 
Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) 
should not be used to provide information necessary to the review because 
reviewers are under no obligation to view the Internet sites.   Furthermore, 
we caution reviewers that their anonymity may be compromised when they 
directly access an Internet site.

HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to 
achieving the health promotion and disease prevention objectives of "Healthy 
People 2010," a PHS-led national activity for setting priority areas. This PA 
is related to one or more of the priority areas. Potential applicants may 
obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health 
Systems Agency review.  Awards are made under the authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All 
awards are subject to the terms and conditions, cost principles, and other 
considerations described in the NIH Grants Policy Statement.  The NIH Grants 
Policy Statement can be found at 
http://grants.nih.gov/grants/policy/policy.htm 

The PHS strongly encourages all grant recipients to provide a smoke-free 
workplace and discourage the use of all tobacco products.  In addition, 
Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in 
certain facilities (or in some cases, any portion of a facility) in which 
regular or routine education, library, day care, health care, or early 
childhood development services are provided to children.  This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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